Phenformin has a direct inhibitory effect on the ATP-sensitive potassium channel

The biguanides, phenformin and metformin, are used in the treatment of type II diabetes mellitus, as well as being routinely used in studies investigating AMPK activity. We used the patch-clamp technique and rubidium flux assays to determine the role of these drugs in ATP-sensitive K+ channel (KATP) regulation in cell lines expressing the cloned components of KATP and the current natively expressed in vascular smooth muscle cells (VSMCs). Phenformin but not metformin inhibits a number of variants of KATP including the cloned equivalents of currents present in vascular and non-vascular smooth muscle (Kir6.1/SUR2B and Kir6.2/SUR2B) and pancreatic β-cells (Kir6.2/SUR1). However it does not inhibit the current potentially present in cardiac myocytes (Kir6.2/SUR2A). The highest affinity interaction is seen with Kir6.1/SUR2B (IC50 = 0.55 mM) and it also inhibits the current in native vascular smooth muscle cells. The extent and rate of inhibition are similar to that seen with the known KATP blocker PNU 37883A. Additionally, phenformin inhibited the current elicited through the Kir6.2ΔC26 (functional without SUR) channel with an IC50 of 1.78 mM. Phenformin reduced the open probability of Kir6.1/SUR2B channels by ∼ 90% in inside-out patches. These findings suggest that phenformin interacts directly with the pore-forming Kir6.0 subunit however the sulphonylurea receptor is able to significantly modulate the affinity. It is likely to block from the intracellular side of the channel in a manner analogous to that of PNU 37883A.